Contrave (Naltrexone/Bupropion)

Contrave is an extended-release (ER)  combination product containing naltrexone, an opioid antagonist, and bupropion, an  antidepressant  The Food and Drug Administration (FDA) has approved Contrave  in September 2014 after adequate clinical trials demonstrated its safety and efficacy.

The exact neurochemical mechanism of the naltrexone/bupropion combination leading to weight loss is not fully understood. However, from preclinical study data, the combination is theorized to work synergistically in the hypothalamus and the mesolimbic dopamine circuit to promote satiety, reduce food intake, and enhance energy expenditure.

Pro-opiomelanocortin (POMC) cells found in the arcuate nucleus of the hypothalamus produce melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin, an endogenous opioid. The alpha-MSH activates the melanocortin-4 receptor (MC4R), leading to decreased food intake, increased energy expenditure, and weight loss. Beta-endorphin reduces activity of POMC cells by binding to the inhibitory mu-opioid receptor (MOP-R). Bupropion, a weak dopamine and norepinephrine reuptake inhibitor, enhances POMC cell production and release of alpha-MSH and beta-endorphin in vitro. Naltrexone, an opioid antagonist, blocks the MOP-R, therefore disrupting beta-endorphin inhibitory feedback on POMC cells. The naltrexone/bupropion combination enhances the effect of POMC signaling more than either drug alone.

Naltrexone/bupropion is indicated as an adjunct to increased physical activity and a reduced-calorie diet for chronic weight management in obese adults (BMI of 30 kg/m2 or greater) or in overweight adults (BMI of 27 kg/m2 or greater) with at least one weight-related comorbid condition, such as hypertension, type-2 diabetes, or dyslipidemia.

Dosing recommendations are based on the number of tablets, which contain 8 mg of naltrexone and 90 mg of bupropion. Contrave should initially be prescribed as one tablet taken by mouth in the morning for one week. At the start of week 2, another tablet should be added to the regimen in the evening. This titration should continue weekly until the optimal dosing of two tablets twice daily is reached at week 4 for a total daily dose of 32 mg of naltrexone and 360 mg of bupropion.

After 12 weeks of treatment with naltrexone/bupropion, a patient should have achieved at least a 5% weight loss since initiation of therapy. If this result is not attained within 12 weeks, then naltrexone/bupropion should be discontinued because it is unlikely that the patient will derive benefit from it.

Drug Interactions :    The naltrexone component of Contrave may prevent patients from achieving full benefit from opioid-containing medications such as cough suppressants, antidiarrheal drugs, or opioid analgesics. If a patient requires intermittent treatment with opioids, Contrave should be discontinued and standard doses of the opioid should not be exceeded. If a patient uses opioids chronically, the opioid should be discontinued for seven to 10 days before Contrave is initiated to prevent precipitation of opioid withdrawal.  

Bupropion may cause seizures in some patients.